We will employ experimental embryology to investigate cell contact and adhesion to extracellular matrix (ECM) during cardiac morphogenesis. Understanding cell:ECM interactions will help explain how mesodermal cells assemble a tubular heart from the pre-cardiac primordia. The working hypothesis of this proposal is that cellular interactions with ECM are required for morphogenesis of the endocardial tube and the endocardial cushions (valvular and septal primordia). According to this hypothesis, molecular recognition mechanisms mediate cell adhesion to specific structural moieties in the ECM. These recognition sites constitute a solid phase of information that cells require to assemble a new heart. In other words, binding to ECM molecules in precise ways represents an adhesion code that determines the behavior of mesodermal cells during heart tube formation. Cell contact and adhesion during morphogenesis are likely to regulate several kinds of activity, including: cell shape change, motility, exertion of tractional forces, response to growth factors, and degradation/synthesis of ECM. We propose to investigate our adhesion code hypothesis using avian embryos ranging from early pre-cardiac stages to formation of valve rudiments. Specifically we are interested in examining cardiac vasculogenesis and the formation of endocardial cushions. The experimental aims are: 1) to inject early embryos with biological agents such as ECM antibodies; ECM receptor antibodies, and synthetic ECM ligand peptides that are likely to perturb cell contact/adhesion; 2) to study the cellular lineages of pre-cardiac splanchnic mesoderm; 3) to prepare monoclonal antibodies that inhibit angioblast adhesion to ECM, and subsequently, to use these antibodies according to aim #1. There are several potential heath benefits that could be realized by this proposed work: First, experimentally induced deficiencies in cell adhesion may explain some categories of cardiac malformations. Second, understanding the molecular mechanisms of cell contact and adhesion will provide the information necessary to design therapies for the repair and remodeling of cardiac anomalies. Finally, cell lineage analysis will identify progenitor cells that may be capable of repairing tissue defects.
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